PCT/IB98/00151 incorporated herein by reference, describes the synthesis and biological activity of atropisomers of 3-heteroaryl-4(3H)-quinazolines.
Atropisomers are isomeric compounds that are chiral, i.e. each isomer is not superimposable on its mirror image and the isomers, once separated, rotate polarized light in equal amounts but opposite directions. Atropisomers are distinguished from enantiomers in that atropisomers do not possess a single asymmetric atom. Atropisomers are conformational isomers which occur when rotation about a single bond in the molecule is prevented or greatly slowed as a result of steric interactions with other parts of the molecule and the substitutents at both ends of the single bond are unsymmetrical. A detailed account of atropisomers can be found in Jerry March, Advanced Organic Chemistry, 101-102 (4th ed. 1992) and in Oki, Top. Stereochem., 14, 1-81 (1983).
The compounds of PC9803 provide the first evidence that atropisomers of quinazolinones are seperable and that the separated isomers possess differential AMPA receptor antagonist activity. (AMPA receptors are a subspecies of the glutamate receptors, identified by their ability to bind .alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), that are post synaptic neurotransmitter receptors for excitatory amino acids.) Colebrook et al., Can. J. Chem., 53, 3431-4, (1975) observed hindered rotation about aryl C--N bonds in quinazolinones but did not separate or suggest that the rotational isomers could be separated. U.S. patent application Ser. No. 60/017,738 filed May 15, 1996 and entitled "Novel 2,3-Disubstituted -4-(3H)-Quinazolinones" and U.S. patent application 60/017,737 filed May 15, 1996 and entitled "Novel 2,3-Disubstituted -(5,6)-Heteroarvlfused-Pyramidin-4-ones," both applications herein incorporated by reference in their entirety, refer to racemic quinazolinones and pyrimidones. The inventors of PCT/IB98/00151 discovered that one quinazolinone isomer, defined by the spatial positions of the substituents arising out of steric interactions, possesses all of the AMPA receptor antagonist activity.
The role of excitatory amino acids, such as glutamic acid and aspartic acid, as the predominant mediators of excitatory synaptic trasnmission of the central nervous system has been well established. Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21,165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). These amino acids function in synaptic transmission primarily through excitatory amino acid receptors. These amino acids also participate in a variety of other physiological processes such as motor control, respiration, cardiovascular regulation, sensory perception, and cognition.
Excitatory amino acid receptors are classified in to two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic." This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methylisoxazole-4-proopionic acid (AMPA), and Kainic acid (KA). The second general type is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocuclopentane-1 ,3-dicarboxylic acid, leads to enhanced phosphoinosoitide hydrolysis in the postsynaptic connection during development and changes in the efficiency of synaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek. Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by a way of a mechanism known as excitotoxicity. The process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neoronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions including cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, epilepsy, Aids-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowing, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, ocular damage and retinopathy, and idiopathic and drug-induced Parkinson's Disease. Other neurological conditions, that are caused by glutamate dysfunction, require neuromodulation. These other neurological conditions include muscular spasms, migraine headaches, urinary incontinence, psychosis, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), opiate tolerance, anxiety, emesis, brain edema, chronic pain, convulsions, retinal neuropathy, tinnitus and tardive dyskinesia. The use of a neuroprotective agent, such as an AMPA receptor antagonist, is believed to be useful in treating these disorders and/or reducing the amount of neurological damage associated with these disorders. The excitatory amino acid receptor (EAA) antagonsts are also useful as analgesic agents.
Several studies have shown that AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxoline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al., Science, 247, 571 (1900); Buchan et al., Neuroreport, 2, 473 (1991); LePeillet et al., Brain Research, 571, 115 (1992). These studies stronly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in art by AMPA receptor activation. Thus, AMPA receptor antagonists may prove useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in humans.
The preparation of 3-(2-chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)]-vinyl-6-fluoro -3H-quinazolin-4-one from 6-[2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl] -pyridine-2-carbaldehyde and diethylamine in the presence of sodium triacetoxyborohydride is described in PCT/IB98/00151.